HEALTH


Research is also now focusing on immune cells called microglia. Accounting for up to 15% of brain cells, microglia deal with cell maintenance, hoovering up plaques, damaged neurons and infectious agents. Schwartz’s lab has shown that


two types of ‘glial cells’ – microglia and astrocytes – become active in the hypothalamus in rats obese from a high fat diet. The ‘gliosis’ was detectable days after the rats began their high fat diet. Researchers from the University


of California, San Francisco (UCSF) and the University of Washington in the US suggest the microglia act as sensors for saturated fat.3


They are


an untapped way to target the brain for potential obesity treatments, suggests co-author Suneil Koliwad from the UCSF Diabetes Center. Led by Joshua Thaler, the team fed


mice a fat-rich diet for four weeks. Not only did the mice eat more, burn fewer calories, and gain more weight than those on a low-fat diet, they also had more microglia, which triggered brain inflammation. The researchers then reduced the number of microglia using an experimental drug from Californian biotech firm Plexxikon. While the drug did not affect weight gain in mice fed a normal diet, treated mice on a high-fat diet ate 15% less food and did not gain as much weight as untreated mice on the same diet. When the team genetically engineered mice to stop microglia activating inflammatory responses, the mice also consumed fewer calories and gained less weight. GM mice given a drug to activate


the microglial inflammatory response ate 33% more food, leading to a four-fold increase in weight gain, compared with untreated mice on the same healthy diet. Next, the researchers intend to


investigate exactly how the microglia are activated and whether there are ways to block the signals.


AGE-related The answer could lie in chemicals called advanced glycation end- products (AGEs) that form when sugars and free amino groups in proteins react together either during cooking or in the body. AGEs cause oxidative stress and inflammation. They are associated


15%


If neurons die, your brain is out of control of food intake. You just feel hungry and you want to eat all the time. And you don’t burn off fat anymore because there is no driving force for the brain to stimulate fat burning


Chun-Xia Yi, University of Amsterdam


The reduction in food intake by mice fed a high-fat diet and treated with an experi- mental drug that re- duces levels of immune cells called microglia. Research suggests microglia could act as biological sensors for saturated fat.


Non-digestible carbo- hydrates such as inulin reduce appetite and weight gain through microbial fermenta- tion. Such fermentable carbohydrates are found in vegetables such as onions and artichokes, and inulin supplements grace the shelves of many health food shops.


with ageing processes, such as wrinkle formation, while others may be a factor in diabetes and Alzheimer’s disease. Working with German researchers


from the Helmholtz Diabetes Centre and Munich University, Chun-Xia Yi from the Academic Medical Center, University of Amsterdam, in the Netherlands, has monitored levels of an AGE called carboxymethyllysine (CML) in mice fed a high sugar-high fat diet for one month.4 ‘It’s like someone only eating fast


food and cola for three months,’ she jokes.


In the brain, neurons can produce CML as metabolic waste. Eating high sugar and high lipid foods together appears to make them produce more CML, says Yi. The AGE binds to a protein and is soon secreted by the neurons. Microglia then attempt to clean up


the CML, but in the process produce inflammatory chemicals such as cytokines, which act on neighbouring neurons. These then produce more metabolic waste. ‘It’s a feedback loop between neurons and microglia,’ says Yi.


The neurons responsible for


controlling food intake eventually die. ‘If neurons die, your brain is out of control of food intake. You just feel hungry and you want to eat all the time. And you don’t burn off fat anymore because there is no driving force for the brain to stimulate fat burning,’ says Yi. To maintain or lose weight, Yi


recommends avoiding eating fats and sugars/carbohydrates together. Using tissue from The Netherlands


Brain Bank, the team now wants to explore whether the results transfer to humans. With a large family of AGEs, the chances are that different but related substances may play key roles in humans. The ultimate goal is to find a way


to dampen microglial activity to stop them producing too many cytokines. ‘The destination is not AGE itself but how to get the cells to clear up the AGEs more efficiently,’ says Yi. AGEs are difficult to study because they are present in many cooked, protein-rich food products. Separating the contribution of calories and AGEs to obesity is a tricky task. Nevertheless, a team led by Jaime Uribarri and Weijing Cai from the Icahn School of Medicine at Mount Sinai, New York, US, has correlated AGE levels and some aspects of metabolic syndrome, including inflammation and insulin resistance. Metabolic syndrome is a cluster of


conditions, such as high blood sugar levels and excess body weight, which increase the risk of Type 2 diabetes and cardiovascular disease. The researchers found higher levels of AGEs in obese people showing some features of metabolic syndrome. Obese people without the symptoms had lower AGE levels, leading the researchers to suggest that high dietary AGE consumption could perhaps cause ‘at-risk obesity’ - as opposed to ‘healthy obesity’.5 Meanwhile, Williams plans to run a human study on AGEs, using milkshakes, which are packed full of protein and sugar and lipids and so induce more AGEs. Her team plans to look at how quickly volunteers clear lipids and glucose.


Fatty fermentation The role of hormonal and neuronal signals in regulating appetite is inextricably linked to gut microbes and fermentation of dietary fibre. Research suggests that non- digestible carbohydrates such as inulin reduce appetite and weight gain through microbial fermentation. Fermentable carbohydrates


are found in vegetables such as onions and artichokes, and inulin supplements grace the shelves of many health food shops. ‘Yet if you try to supplement


inulin into people’s diets there is very poor compliance because there


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